Several NIH Institutes and the Knockout Mouse Project (KOMP) announce the opportunity for investigators to apply for administrative supplements to have mouse knockouts made from existing mutant ES cell resources. The goal of this program is to support use of existing resources and to ensure that ES cell lines are converted into frozen embryos that are available from a repository.

Background

The attendees at an international meeting convened in the Fall of 2003, at the Banbury Conference Center, Cold Spring Harbor, New York, strongly supported the establishment of a focused, large-scale international effort to produce a publicly available, comprehensive collection of mouse knockout alleles, i.e., a library containing a null mutation in every gene in the mouse genome (Austin, C.P, et al. Nature 36, 921-924, 2004). The attendees also recommended a phased production approach beginning with the construction of a resource of mutant ES cells. It was also discussed that improving access to existing resources would avoid unnecessary duplication of efforts. Since the Banbury meeting, significant progress has been made toward generating the mutant resource envisioned by the attendees. Several gene targeting consortiums, the European Conditional Mouse Mutagenesis Program (EUCOMM), the Canadian North American Conditional Mouse Mutant Resource (NORCOMM) and a trans-NIH program, the Knockout Mouse Project (KOMP), have been funded to complete the mouse mutant resource. ES cells and mice from the latter will begin to be available by Spring 2007.

In recognition of the research community’s keen interest in utilizing knockout mice in their research programs and to optimize usage of the extensive resource now available to the research community, several NIH Institutes and the Trans-NIH KOMP announce an administrative supplement program. This program is designed to enable NIH-funded researchers to request support to have mice of interest made from existing mutant ES cell resources available from both the public and private sectors. This effort will make important mouse mutants available to research laboratories. Additionally, producing the mice in a central facility (as proposed below) will ensure that the mice will be deposited in the KOMP repository, or another NIH supported repository where they will be available to the entire research community.

The application

As stated above, the purpose of this program is to support and accelerate currently funded NIH research programs’ access to mice needed for their research by utilizing the extensive existing collections of mutant ES cell lines. Therefore, the most important element of the request will be the scientific justification for the request. Supplements may not be requested to expand the scope of the project as approved. The requestor must justify acquisition of the knockout mouse as furthering the original approved aims of the grant. Within these limits, manyjustifications for the request can be envisioned, for example: 1) A scientist working on a specific gene or pathway related to a human disease may request that a mouse be made from an ES cell containing the knockout of that gene or member of that pathway; or 2) A scientist working on a gene in another model organism may request that a mouse be made from an ES cell containing the knockout for that gene providing that they or a collaborator has the appropriate expertise using mice. There are many other appropriate justifications for requests; those listed are meant to be illustrative. Applicants must contact their Institute Program Director to ask if there are Institute specific policies they must address in the request. Requests will be evaluated by the program staff of each participating Institute for prioritization and funding according to the criteria given below. Due to the limited funds available for this program, only the most scientifically compelling requests will be funded.

Publicly available knockout ES cell collections that are available or will be available to participate in this program are:
1) the Baygenomics and Sanger IGTC ES cells http://www.mmrrc.org/distribution/cellLines.html), 2) Omnibank I and Omnibank II available from The Institute for Genomic Medicine (TIGM, http://www.tigm.org/) 3) EUCOMM (http://www.eucomm.org/) and 4) KOMP (http://www.knockoutmouse.org/) . Other organizations with knockout ES cell collections may participate if they are willing to accept the KOMP MTA (which can be obtained upon request) and other conditions set out by this program. Applications must contain evidence that the requesting investigator has contacted the ES cell repository, and the specified ES cell is available to be made into a mouse that will be made available to the mouse research community through the KOMP repository. More than one mutant mouse can be requested per proposal if they are relevant to the same project.

The Repository that holds the ES cell(s) being requested will prepare ES cells for chimera production, perform the injection and breeding, and identify heterozygous founder offspring. A minimum of two offspring will be shipped to the requestor (dependent on the success of the breeding) and the repository will retain enough animals for transfer to the KOMP repository. If another facility prepares the mouse, it must supply the same number of mice to both the KOMP repository and to the Investigator. A letter must be included from the site that will make the mouse indicating: (1) the cost for making the mouse (not to exceed the guidelines of the supplement), (2) that the mice will be shipped to the Investigator and to the KOMP repository with an approximate timeline (number of months from the receipt of order) for supply of the mice, (3) that it will provide production status information for the mouse to NHGRI staff upon request.

Resource & Data sharing

Grantees will comply with NIH policy on resource and data sharing. The plan for sharing the mice made in this program will include a statement from the repository that makes the mouse that it will send animals to the KOMP repository for distribution to the scientific research community with no reach through as specified in the KOMP MTA.

Budget and Funding Information

Supplements will be awarded by the participating ICs as TOTAL COSTS. The NIH share will not exceed $13,125 direct costs, plus indirect costs per mutant. The applicant organization is expected to make up the difference between the funds NIH provides and the cost of the mouse. The Institution must also provide funds for cryopreservation to the NIH-funded repository that will make the mouse mutant available to the research community. This cost is estimated to be ~$2500/mouse. If the total cost requested is less than $13,125 direct costs, then the cost for cryopreservation may be included in the request. In their requests, applicant organizations must verify that funds are available for this purpose. The funds awarded by NIH will be restricted for this use. Applicants who have approved funding to make the requested knockout mouse must explain why a supplement is being requested and the applicant must indicate how the existing grant funds will be utilized if the request for a supplement is approved. Participating Institutes will use the rationale as part of their selection criteria for awarding supplements.

How to apply

Submission of requests should be sent electronically to the KOMP Institute representative (listed below) at a KOMP mail box: mouseKOsupplements@mail.nih.gov with the PI’s name and grant number on the Subject line. NHGRI KOMP staff will track the submissions and send them to the Institute staff designated in the email. Applicants unable to submit an electronic application as noted above will submit a written application addressed to the same KOMP staff contact. Please note: only grantees of Institutes listed above as participating in this program are eligible. Other NIH grantees may contact their Institute Program Director to inquire about participation in the program.
The supplement application will include the following sections in an attached file in MSWord, WordPerfect, or pdf formats:

A cover page citing the NOTICE and requesting an administrative supplement, including the PI name, grant number and title, and amount requested. Please note how many years remain for the funded grant;

A PHS 398 Face Page signed by the authorized organizational representative that includes the name and title of the institutional official, and phone, email, and address information for the PI and institutional official.

A brief budget justification that details the budget items requested, including F&A (direct costs not to exceed $13,125);

A description (2-page limit) specifying the ES cell (repository name and designation used to identify ES cell line) from which the PI would like to have a mutant mouse generated, the utility of the mutant mouse to the original project Specific Aims and its importance in biomedical research in general;

Biographical Sketch of the PI;

Specific Aims from the original grant;

Resource & Data sharing statement;

If injections are not performed at TIGM or the MMRRC a letter from the facility agreeing to the terms above.

Review Procedure

Applications will be reviewed by the participating Institute that supports the PI who submitted the application.

Review criteria

The scientific significance of the mutant for biomedical research in general and its relation to the Specific Aims of the parent grant.

The relevance of the request to program priorities of the institute

Institutional support

Inquiries

Direct questions about the scientific/research issues of the program to: